Pearls in Thrombosis Update for Family Physicians A Case ... · Update for Family Physicians –A...
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Pearls in Thrombosis
Update for Family Physicians – A Case-Based Approach
Sudeep Shivakumar
April 6th, 2018
44th Annual Dalhousie Spring Refresher
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+Conflict of Interest Disclosures
• Pharmaceutical Company Affiliations
• None
• Grants/Research Support
• None
• Speakers Bureau/Advisory Boards
• Pfizer Inc
• Bayer Inc
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+Objectives
To discuss the acute treatment of DVT/PE, including the direct
oral anticoagulants (DOACs)
To briefly discuss perioperative management of DOACs
To discuss the duration of anticoagulation for DVT/PE
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+Case
23 year old female, G0P0
Dalhousie student
Previously healthy
Notes right calf cramps when walking the dog
Over the next 3 days, also notes swelling of the calf
Over the next 2 days, entire right leg swells up
Presents to GP
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+Case
No history of trauma, immobility or surgery
No recent travel
Did start oral contraceptive Alesse last month
No family history of DVT/PE
No previous history of DVT/PE
No symptoms of PE
No constitutional symptoms
Full PMHx, meds, allergies, social history
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+Case
Exam shows:
HR 86 reg, BP 122/70, sats 99% room air, RR 22
Chest clear
CVS: Normal JVP, normal S1S2, no murmurs
Abdomen benign
Right leg red, warm, swollen with pitting edema, and ++ tender
Whole leg is swollen
Distal pulses are strong and present
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+Case
Sent immediately to ED
CBC shows normal hemoglobin and platelets
Creatinine normal
Pregnancy test negative
Given dose of dalteparin 200 units/kg
Appointment for ultrasound next AM
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+Case
Presents for U/S next morning
Confirms presence of extensive right leg DVT
Thrombus seen from popliteal vein to superficial femoral vein,
extending into iliofemoral system
Sent to Hematology clinic for management
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+Case
Questions:
Which anticoagulant would you start her on?
How long would you treat her for?
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+Venous thromboembolism
Deep venous thrombosis Pulmonary embolism
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+Venous thromboembolism
Not uncommon
Incidence of 1st time VTE = 1.92 per 1000 person years
Major cause of morbidity and mortality
6% of deceased patients had evidence of massive pulmonary
embolism
1Cushman, Am J Med, 2004
2Dismuke, JAMA, 1986
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+Pulmonary embolism
Untreated PE
Mortality rate of ~30%1
Most die within hours of diagnosis
Treated PE
Prospective NEJM study looked at 399 patients with newly
diagnosed PE
94% received conventional treatment
Only 2.5% (10 patients) died of PE
1Dalen, Prog Cardiovasc Dis, 1975
2Carson,NEJM, 1992
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+Treatment of DVT/PE
Goals of treatment:
Short term:
Prevent the extension of thrombus
Prevents embolization of DVT
Reduce mortality for PE by reducing recurrent events
Relief of symptoms
Long term:
Prevent recurrent events
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+Standard initial treatment?
Start with low molecular weight heparin
Enoxaparin 1.5 mg/kg subcut daily
Dalteparin 200 units/kg subcut daily
Tinzaparin 175 units/kg subcut daily
Round to prefilled syringe dose
Most patients can be taught to do self-injections
Start as soon as diagnosis suspected
First 24 hours most risky time for untreated PE
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+Standard initial treatment?
Warfarin can be started on day 1
Lots of nomograms available
10mg orally for 2 days is safe in most patients
Do not stop LMWH until minimum 5 days, and 2 days overlap
with INR therapeutic (2-3)
Hypercoagulable state in first few days
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+Case
She has a severe needle phobia
Has trouble even getting dalteparin injection in ED
Asks about other options
“What about that blood thinner I saw an ad on CNN?”
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+Difficulties with warfarin use
Requires monitoring
Numerous drug and diet interactions
Narrow therapeutic range
Difficult to control – takes time to get in or out of the system
Role for new anticoagulants?
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+An ideal oral anticoagulant…
No monitoring
Few interactions
Short onset/offset
Reversible
Efficacious
Safe
✓
✓
✓
✓
✓
✓
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+Warfarin…
No monitoring
Few interactions
Short onset/offset
Reversible
Efficacious
Safe
X
X
X
✓
✓
✓
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+The direct oral anticoagulants…
No monitoring
Few interactions
Short onset/offset
Reversible
As efficacious
As safe
✓
✓
✓
X
?
?
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+New anticoagulants
Leung, The Hematologist, 2011
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+New (direct) oral anticoagulants
Predictable pharmacokinetics
No need for monitoring
Less interactions with medications and food
Direct thrombin inhibitors
Dabigatran
Factor Xa inhibitors
Rivaroxaban
Apixaban
Extensively studied in atrial fibrillation (and now DVT/PE!)
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+
Drug Inhibitor of LMWH
bridging
Recurrent VTE Bleeding
Rivaroxaban Factor Xa No Non-inferior Non-inferior
Dabigatran Direct
thrombin
Yes Non-inferior Non-inferior
Apixban Factor Xa No Non-inferior Decreased
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PHARMACOKINETIC PROPERTIES AND
NEW ANTICOAGULANTS
PropertyNew Anticoagulants
Dabigatran Rivaroxaban Apixaban
Bioavailability
(F rel)6.5% 80% 80%
Peak action
(t max)1-3 hrs 1-3 hrs 1-3 hrs
Elimination
half-life (t ½)14-17 hrs
9-15 hrs 9-14 hrs
Route of
clearance80% renal 65% renal 25% renal
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+Direct oral anticoagulants
As good and as effective as LMWH/warfarin for acute VTE
May be trend towards less bleeding
Specifically, less intracranial bleeding
May not have to use LMWH bridging (rivaroxaban, apixaban)
Caveats:
No antidote… except dabigatran
Still some drug interactions
Cost
Need adequate creatinine clearance (>30 mL/min)
Not known how they work in pregnancy - AVOID
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+Dosing
Rivaroxaban*
15 mg BID x 3 weeks, then 20 mg daily
Apixaban*
10 mg BID x 1 week, then 5 mg BID
Dabigatran
LMWH x 10 days, then dabigatran 150 mg BID
All are around $3 per day
*Covered by Pharmacare for 6 months only
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+Case
She goes on a DOAC and does well with it
However, she develops abdominal discomfort and weight loss,
and is referred to gastroenterology, who wish to perform upper
and lower endoscopy
How should her DOAC be managed for the procedure?
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+Perioperative management of direct
oral anticoagulants
Based on three major factors:
Elimination half life of the drug
Renal function
Bleeding risk of surgery (and type of anaesthesia)
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+PHARMACOKINETIC PROPERTIES AND NEW
ANTICOAGULANTS
Property
New Anticoagulants
Dabigatran Rivaroxaban Apixaban
Bioavailability
(F rel)6.5% 80% 80%
Peak action
(t max)1-3 hrs 1-3 hrs 1-3 hrs
Elimination
half-life (t ½)14-17 hrs
9-15 hrs 9-14 hrs
Route of
clearance80% renal 65% renal 25% renal
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+Pre-op
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+Perioperative management of new
anticoagulants
In practice (what we do)…
Stop all new agents 2 days before (last dose 3 days prior) if
creatinine clearance is adequate (>50 ml/min)
Based on the fact that all agents have elimination half lives <17
hours
Can stop 1 day prior for low bleeding risk surgery
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+Post-op
Option to use low dose dabigatran or bridging LMWH is felt full dose NOAC to be delayed
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+Case
6 months later, she has had significant improvement in leg
swelling and resolution of her pain
No signs of significant post-thrombotic syndrome
She leads an active lifestyle, and wants to get off blood
thinners
Aware of risk of recurrent events
Wants to play ultimate and soccer again!
Can she stop anticoagulation?
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+Duration of anticoagulation
Provoked DVT/PE
3 months and then stop (grade 1B)
<1% per year risk of recurrent events
Unprovoked DVT/PE
3 months minimum (grade 2B – in Canada, most treat 6 months)
If high bleeding risk, consider stopping
If low bleeding risk, consider long term anticoagulation
Risk of recurrence ~12-15% in the first year
2nd unprovoked DVT/PE
Lifelong anticoagulation
Chest guidelines, 2012
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+Summary
VTE is common and has a high mortality
DOACs have growing body of evidence for acute and long term
treatment of DVT/PE
Three agents currently approved
Duration of anticoagulation a controversial area
3 months and stop for provoked events
3-6 months and consider continuation for unprovoked events
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+Thank you!